2019/098551 1»（：1^1{2018/012575
【Explanation of the invention】

【Name of invention】

Manufacturing method of intermediate compound for pharmaceutical synthesis

【Technical field】

Mutual citation with the relevant application(s)

This application claims the benefit of priority based on Korean Patent Application No. 10-2017-0153334 filed on November 16, 2017 and Korean Patent Application No. 10-2018-0126663 filed on October 23, 2018. All content disclosed in the literature is included as part of this specification.

The present invention relates to a preparation method of Formula 1, which is an essential intermediate for synthesizing dipeptidyl peptidase IV (hereinafter, referred to as '卵! 3 -') inhibitory diabetes treatment agent.

【Technology behind the invention】

International application publication ¥) Dipeptidyl peptidase (卵! 3- ) disclosed in 12/030106 is a compound useful as a therapeutic agent for diabetes (International Application Publication 0

12八) See the compound of Formula 1 in No. 30106) 0??-^ It is known that it exhibits excellent inhibitory activity against enzymes and can be effectively used for the treatment and prevention of diseases such as diabetes and obesity, which are diseases caused by the enzyme. In the preparation of such an inhibitor compound, International Patent Publication No. 0 12八) 30106 discloses a method for preparing from the following Formula 1 compound as an essential intermediate.

[Formula 1]

Meanwhile, conventionally, in order to prepare the compound of Formula 1, the carboxylic acid protecting group (¾) of the compound of Formula 2 was obtained by performing a deprotection reaction. Specifically, in the case of the compound of Formula 2 in which the protecting group is butyloxycarbonyl 0, 如 and the leaving group is 卜butyl group (IV) in the above formula (1) acidic conditions, specifically, a strong acid such as sulfuric acid, dichloromethane, aqueous sodium hydroxide solution, and Di-tert-butyl dicarbonate (¾ ¾ ⑴ is used to hydrolyze the protecting group ¾ for deprotection, or (2) basic conditions, specifically, sodium hydroxide aqueous solution, ethanol, water reflux 2019/098551 1»（：1 ^1{2018/012575

It was prepared by hydrolysis of protecting group 2 using conditions and deprotection. In particular, in the case of ¾ is a benzyl group, a methyl group, an ethyl group, and a propyl group, the hydrolysis conditions using the base specified in (2) were used among the above two conditions.

[Formula 2]

However, the preparation method of the compound of Formula 1 has the disadvantage that the reaction proceeds only when the reaction proceeds under somewhat severe conditions, a large amount of reaction solvent must be used, and an additional concentration process is required.

【Contents of the invention】

【Task to be solved】

Accordingly, the present inventors have conducted intensive research in order to solve the above-described disadvantages of the prior art. As a result, when sodium hydroxide is used in a solid form among bases, the yield can be remarkably improved even under mild conditions, and a small amount It was confirmed that economical efficiency and productivity were high because it was economical by using the reaction solvent of

Therefore, in the present invention, in preparing the compound of Formula 1, which is an intermediate used for synthesizing an inhibitory diabetes therapeutic agent, unlike conventional methods, using sodium hydroxide under basic conditions, the yield can be remarkably improved even under mild conditions, The purpose is to provide a synthetic method with high economical efficiency and high productivity without the need for an additional concentration process while being economical by using a small amount of reaction solvent.

【Measures for solving problems】

As an aspect for solving the above problem, the present invention relates to a method for preparing a compound of Formula 1, wherein the method for selectively deprotecting a carboxylic acid protecting group (¾) among two protecting groups and ¾ protecting groups of the compound of Formula 2 It includes a step of reacting, wherein the deprotection reaction is characterized in that it is carried out using a solid base and a lower alcohol.

【Effects of the Invention】

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The manufacturing method according to the present invention, the compound of Formula 1, which is an intermediate for oral insulin-independent diabetes treatment through inhibition, 1) can be produced in high yield even under mild conditions, and 2) cost can be reduced by reducing the amount of reactive solvent used. It is economical because it can be used. 3) It is very useful as it has the advantage of achieving improvement effects such as productivity increase through elimination of the concentration process.

【Specific contents for implementing the invention】

Hereinafter, the present invention will be described in detail based on the reaction formula. However, the following reaction formula is only intended to aid understanding of the present invention, and is not intended to limit the present invention in any sense.

When the manufacturing method according to the present invention is specifically described, it is shown in Scheme 1 below.

[Scheme 1]

In the above formula, 1 to 2, parent 3 and seed 4 are each independently hydrogen, halogen, substituted or unsubstituted 0 1 0 4 alkyl. ^ Is a carbonyl group, acyl group, sulfonyl group, acetyl or benzyl group as an amine protecting group, preferably
此(：(butyloxycarbonyl), 0^(benzyloxycarbonyl) or 1¾ 0 ( ：( 9-fluorenyl) Methyloxycarbonyl), more preferably 80 (:). ? 2 is a carboxylic acid protecting group, preferably a benzyl group, a methyl group, an ethyl group, a propyl group, or a ^butyl group, and more preferably a 1:-butyl group.

In the present invention, when obtaining the compound of Formula 1 through a deprotection reaction of the carboxylic acid protecting group (¾) of the compound of Formula 2 under conventional basic conditions, unlike the use of an aqueous solution or a liquid base such as an aqueous sodium hydroxide solution As a feature of the invention, the use of a base in a solid form. The solid base used in the present invention may be sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, or a combination thereof, and preferably sodium hydroxide solid is used to obtain the compound of formula 1.

The amount of the reaction base used is preferably 1 to 4 equivalents, preferably 1 to 2 equivalents based on the compound of Formula 2.

5

In addition, as a reaction solvent used in the above reaction, a lower alcohol having 1 to 6 carbon atoms and a mixed solvent thereof are used. Specifically, lower alcohols of the carbon number of 1 to 6 is be at least one selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, and a mixed solvent thereof the group consisting of (Co-solvent) 0 , and preferably to use ethyl alcohol have. The amount of the reaction solvent is preferably 1 fold (mL/g) to 7 fold (mL/g), preferably 2 fold (mL/g) to 3 fold (mL/g) for the compound of Formula 2. The reaction solvent of the present invention is characterized by using a small amount of the reaction solvent, unlike the conventional preparation method of Formula 1 according to inexpensive conditions.

5

Specifically, the reaction temperature during the deprotection reaction may vary depending on the reaction conditions, but in the case of the present invention , the reaction may be performed at a temperature lower than the reflux condition due to technical characteristics, for example, 30 to 80 ° C. The reaction time may preferably be within 1 hour to 6 hours, more preferably within 3 hours and 0, but is not limited thereto.

As an additional aspect, the manufacturing method according to the present invention may further include the step of crystallizing the compound of Formula 1 obtained according to the above. The solvent used for crystallization may be one or more solvents selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, and 5 mixed solvents thereof (Co-solvent), but is not limited thereto, and preferably It is water or a mixed solvent of ethyl alcohol and water. In the crystallization step, the pH can be adjusted by using an acid to form crystals, and the preferred pH is 2.5 to 3.0.

0 Hereinafter, the present invention will be described in more detail through Preparation Examples and Examples, but it is only intended to aid understanding of the present invention, and the scope of the present invention is not limited by these in any sense.

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[Execution ^!]

Example 1: (3S)-3-t-butoxycarbonylamino- 4- (5, 5 -difluoro- 2-oxopiperidino) butanoic acid ((3S) 3-tert-Butoxycarbonylamino-4 -(55 -dif 1 uor Q-2- XOP i per idi no) butanoic acid) synthesis

Starting material butyl (3¾-3-1;-butoxycarbonylamino- 4-(5, 5 -difluoro- 2-oxopiperidino butanoate 462.3
ethyl alcohol 729.6
sodium hydroxide)

82.2 After being introduced into the reactor at room temperature, the temperature was raised to a range of 40-50° [and allowed to react for 3 hours. Water 3699 after completion of the reaction

Add it dropwise
and adjust it to -3.0
The resulting title compound was filtered, washed with a mixture of water and ethyl alcohol and 卜butyl methyl ether, and dried to prepare 347.6 1¾ (content: 97.5%, yield: 85.5%) of the title compound.

¾ ■ (500 mz, E- ( 16) 5 1.32 (A) , 2.20-2.43 (A),

3.26-3.31 細， 況), 3.61 (US, mine), 3.81 細, mine), 4.02 細， mine), 6.73 (1, mine), 12.16 (my).

Example 2: (3-3-卜butoxycarbonylamino-4-(5.5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3-tert-Butoxycarbonylamino-4-(5.5 -dif luoro-2-oxopiperidino) butanoic acid) synthesis

I did. After completion of the reaction, it was concentrated, and 1649 kg of water was added to dissolve it. The aqueous layer was washed with 1221.8 kg of t-butyl methyl ether, and a 3N hydrochloric acid aqueous solution was added dropwise to adjust the pH to 3.0-3.5, followed by a crystallization process. The title compound produced as a solid was filtered, washed with water and t-butyl methyl ether, and dried to prepare 309.8 kg (content: 97.4%, yield: 85.4%) of the title compound.

Example 3: (3S)-3-t-butoxycarbonylamino-4-(5.5-difluoro-2-oxopiperidino)butanoic acid ((3S) ~3~t er t -But oxycar bony 1 am i no-4- (5,5- dif 1 uoro-2-oxop i per idi no) butanoic acid) synthesis

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After completion, it was concentrated, and 172.0 g of water was added thereto to dissolve. 33.9 g of ethyl alcohol was added, and a 3N aqueous hydrochloric acid solution was added dropwise to adjust the pH to 4.1-5.0 first and 2.5 to 3.0 secondly, and the crystallization process was measured. The title compound formed as a solid was filtered, washed with a mixture of water and ethyl alcohol, and dried to give 35.5 g (content: 93.0%, yield: 89. 湖) of the title compound.

Example 5: (3S)-3-t-butoxycarbonylamino-4-(5.5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3-tert-Butoxycarbony1amino-4- (5.5-difluoro-2-oxopiperidino) butanoic acid) synthesis

Starting material t-butyl (3S)-3-t_butoxycarbonylamino- 4-(5, 5 -difluoro- 2-oxopiperidinobutanoate 43.0 g, ethyl alcohol 67.9 g, sodium hydroxide per 8.8 g Was added to the reactor, and the reaction was carried out by raising the temperature to 70° C. After the reaction was completed, the reaction was cooled, and 344.0 g of water was added thereto. The title compound formed as a solid was filtered, washed with a mixture of water and ethyl alcohol, and then dried to give 37.7 g (content: 92.4%, yield: 94.4%) of the title compound.

Example 6: (3S)-3-t-butoxycarbonylamino-4-(5.5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3~tert-Butoxycarbony1amino-4- (5,5-difluoro-2-oxopiperidino) butanoic acid) synthesis

HO、 0广 人
]

Starting material ^butyl (3幻-3a-butoxycarbonylamino- 4-(5, 5 -difluoro- 2 oxopiperidinobutanoate 43.0 ethyl alcohol 67.9
sodium hydroxide 8.8 sugar was added to the reactor, 301: was reaction mixture was heated to complete the reaction and then cooled, washed with water 344.0 8 . was charged with by dropwise addition of 3N aqueous hydrochloric acid solution primarily

The crystallization process was carried out while adjusting to 4.1 to 5.0 and 2.5 to 3.0 secondly. The title compound produced as a solid was filtered, washed with a mixture of water and ethyl alcohol, and dried to prepare 37.7 g (content: 94.1%, yield: 96.2%) of the title compound.

Experimental Example: (3S)-3-t-butoxycarbonylamino- 4-(5.5-difluoro-2-oxopiperidino)butanoic _ flesh _ ((3S)-3-tert according to the production conditions -But oxy car bony 1 am i no-4-(5.5~di f 1 uor Q-2-QXOP i per idi no) butanoic acid)

In order to compare the yield of the compound of Formula 1 according to the base used, the reaction temperature and the reaction solvent, a compound of Formula 1 was prepared from the compound of Formula 2, but was prepared according to the conditions in Table 1, and the results are also shown in Table 1. Shown in.

【Table 1】

Comparison of yield of chemical formula 1 depending on the base used, the reaction temperature and the reaction solvent

As can be seen from the comparative test results shown in Table 1 above, when a solid base such as sodium hydroxide solid is used as a base in a solid form such as sodium hydroxide solid compared to an aqueous base solution such as sodium hydroxide aqueous solution (Les 4 to 6), the amount of reaction solvent is reduced. And it was confirmed that the reaction at a temperature lower than the reflux condition to obtain the compound of Formula 1 in a higher yield. In the case of reducing the reaction solvent, it is preferable because the productivity can be increased because the compound of formula 1 can be obtained as a solid through acidification using an acid in a mixed solvent of ethyl alcohol and water without the concentration of the solvent after the reaction is completed.
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【Claim Scope】

【Claim 1】

It includes the step of selectively deprotecting the carboxylic acid protecting group 2) of the following formula 2 compound and ?2 protecting group , wherein the deprotection reaction is performed using a solid base as a reaction base and a lower alcohol as a reaction solvent _ Characterized by, the manufacturing method of the following formula 1:

[Formula 1]

In the above formula,

1?1, 1sing , myo3 and myo4 are each independently hydrogen, halogen, substituted or unsubstituted 0 1-04 alkyl,

Is a carbonyl group, an acyl group, a sulfonyl group, an acetyl or benzyl group as an amine protecting group,

? 2 is a benzyl group, a methyl group, an ethyl group, a 卜propyl group or a 1;-butyl group.

[Claim 2]

The method of claim 1, wherein the reaction base is at least one selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, and calcium hydroxide.

【Claim 3】

The method of claim 1, wherein the reaction base is used in the amount of 1 to 4 equivalents based on the compound of Formula 2.

[Claim 4]

The method of claim 1, wherein the reaction solvent is a lower alcohol having 1 to 6 carbon atoms.

[Claim 5]

The method of claim 4, wherein the lower alcohol having 1 to 6 carbon atoms is methyl alcohol, ethyl alcohol, or a mixed solvent thereof (Co-solvent). 【Claim 6】

The method of claim 1, wherein the reaction solvent is used in 1 fold (mL/g) to 7 fold (mL/g) for the compound of Formula 2.

[Claim 7]

The method of claim 1, wherein the deprotection reaction is carried out at a reaction temperature of 30 to 80 °C.

[Claim 8]

The method of claim 1, further comprising the step of further crystallizing the compound of formula 1 obtained by a deprotection reaction.

【Claim 9】

The method of claim 8, wherein the crystallization is characterized in that at least one solvent selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, and a mixed solvent thereof (Co-solvent) is used as the crystallization solvent. Way .